tbuckley/cabot-search huggingface dataset:
Do early phase trials predict clinical efficacy in subsequent phase III biomarker-enriched randomized trials?
Authors: Suji Udayakumar, Sasha Thomson, Albiruni Ryan Abdul Razak, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2022)

3152 Background: Efficacy endpoints of randomized controlled trials (RCT) are commonly used as the basis of regulatory drug approvals. Recently, promising results in early phase trials have resulted in approval of biomarker-targeted therapies. We examined if early phase trial results were associated with efficacy in subsequent biomarker-enriched RCTs. Methods: All cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Trials were eligible if a biomarker was used to select a patient population for treatment with a targeted agent. Associated early phase trials were included if they matched the RCT in treatment setting and patient population. Trials pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We assessed difference in endpoints using summary measures (e.g., average, range). We examined whether early phase trials results were associated with RCT results using logistic regression. Results: The search yielded 2,157 unique phase III RCTs and 27 RCTs met eligibility criteria pairing with associated early phase trials, where 17 RCTs met their primary endpoint. The most common biomarkers were EGFR+ (n = 8), HER2+ (n = 5) and PD-L1 (n = 5). Based on average difference of trial pairs, ORR was similar between trials (1.59%, 95% CI = -2.5-5.6, p = 0.50) and median PFS was slightly higher in early phase trials (1.95 months, 95% CI = 0.91-2.99, p &lt; 0.05). On an individual pair basis, there was large range of variability in the difference between early phase trials and RCTs for ORR (range = -23.9-20.2%) and median PFS (range = -0.8-7.4 months). The probability of the RCT meeting its primary endpoint is 50% or 95%, when the early phase trial ORR is 41.2% (95% CI = 35.2-47.1%) or 77.7% (95% CI = 71.7-83.6%), respectively. Conclusions: Through comparison of early phase trials and subsequent phase III RCT, we found that, overall, ORR has minimal bias in early phase trials, and median PFS appears to be slightly overestimated. Substantial variability in results for trial pairs suggests that, on an individual basis, results in early phase trial can be inconsistent with results in subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs for decision-making as the predictive ability of early phase trials is limited.
<i>BRCA</i> variants and the risk of adverse reactions in patients with ovarian cancer: A single-center real-world study.
Authors: Kemin Li, Rutie Yin
Journal: Journal of Clinical Oncology (2022)

e17530 Background: To study the correlation between BRCA mutation status and the risk of adverse reactions in patients with ovarian cancer. Methods: A real-world study was conducted at the largest gynecological oncology center in western China, the West China Second University Hospital of Sichuan University. The research subjects were patients diagnosed with ovarian cancer who were initially treated in our hospital from January 2016 to January 2020 and had their BRCA gene status evaluated. Multivariate Cox analysis was conducted to investigate the correlation between the BRCA mutation status and adverse reactions in ovarian cancer patients during initial treatment. Results: A total of 349 ovarian cancer patients were enrolled, including 79 patients with pathogenic BRCA variants, resulting in a pathogenic mutation rate of 22.6%. Among these 79 patients, 57 had BRCA1 variants and 22 had BRCA2 variants, yielding a pathogenic mutation rate of 16.3% and 6.3%, respectively. Multivariate COX analysis revealed that pathogenic BRCA variants were not related to the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, during the initial treatment of ovarian cancer. Conclusions: BRCA variants did not increase the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, in ovarian cancer patients during initial treatment.
Bladder-neck sparing robot assisted radical prostatectomy: Step-by step procedure
Authors: F. Sessa, A. Rivetti, R. Campi, R. Nicoletti, P. Polverino, L. Verdelli, A. Pecoraro, P. Barzaghi, S. Morselli, M. Gacci, S. Giancane, V. Li Marzi, A. Sebastianelli, M.L. Gallo, G. Vignolini, S. Serni
Journal: European Urology (2022)
Traffic-related Air Pollution and Lung Cancer Incidence: The California Multiethnic Cohort Study
Authors: Iona Cheng, Juan Yang, Chiuchen Tseng, Jun Wu, Salma Shariff-Marco, Sung-shim Lani Park, Shannon M. Conroy, Pushkar P. Inamdar, Scott Fruin, Timothy Larson, Veronica W. Setiawan, Mindy C. DeRouen, Scarlett Lin Gomez, Lynne R. Wilkens, Loïc Le Marchand, Daniel O. Stram, Jonathan Samet, Beate Ritz, Anna H. Wu
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Although the contribution of air pollution to lung cancer risk is well characterized, few studies have been conducted in racially, ethnically, and socioeconomically diverse populations.
The frequency of rare <i>ALK</i> fusions and their clinical significance in NSCLC.
Authors: Bowen Zhu, Xinlin Zhen, Zeqing Gao, Suo Peisu, Jing Zhang, Wenzhe Fan
Journal: Journal of Clinical Oncology (2022)

e21012 Background: ALK fusion is one of the key driver mechanisms in non-small cell lung cancer. In some case reports, some rare mutant forms have also been found to be active and drug-susceptible. There are few reports on the detection and verification methods of rare ALK fusions. Here, we counted the rare fusions of ALK detected by NGS and verified them by other methods. Methods: We analyzed 184 patients with NSCLC harboring ALK-rearrangement detected by NGS from January 2020 to January 2022. We counted the rare ALK fusion forms, and selected two of them for verification by RNA sequencing or immunohistochemistry. Results: Of the 184 patients with ALK fusion that we included, 105 were female and 79 were male (medium age 53). Most female were non-smokers except one while nearly 50% male were smokers. EML4-ALK fusion accounted for the highest proportion (170, 92.4%), 5 were ALK fusions with other 5’ partners ( C2orf44, KCNG3, KIF5B, KDM5A, DCTN1), 6 were intergenic region- ALK rearrangements, 2 were fusions without transcription initiation region, and 1 was LOC399815 -ALK and ALK-EML4 double fusion. Rare fusion forms accounted for less than 10%. We further verified two of these rare fusion mutations by RNA sequencing or immunohistochemistry. Interestingly, one of the patients with a KCNG3-exon1- ALK-exon20 fusion detected by DNA sequencing was confirmed to be an EML4-ALK fusion by RNA sequencing, and another patient with an intergenic region- ALK fusion was confirmed positive by immunohistochemistry. Conclusions: The vast majority of ALK fusions are EML4-ALK fusions, but there are a small number of other forms of fusions. DNA sequencing, RNA sequencing and ICH may give different conclusions for ALK fusions, which may be limited by the detection method. For some rare fusion forms, a variety of methods can be used to detect whether it is an active ALK fusion form.
Immune-suppressive microenvironment was revealed from NSCLC patients with hyperprogressive disease (HPD) from immunotherapy.
Authors: Zhigong Wei, Min Yu, Weiya Wang, Lin Chen, Qidong Yang, Mingzhe Xiao, Chuang Qi, Wenjing Xi, Shifu Luo, Xingchen Peng
Journal: Journal of Clinical Oncology (2022)

e21109 Background: Immune checkpoint inhibitors (ICIs) demonstrated clear survival benefit in advanced non-small cell lung cancer (NSCLC) and was considered as a standard treatment. However, 10%-20% of ICI treated patients presented hyper-progressive disease (HPD) and shortened OS (&lt; 5 months). In this study, we analyzed the tumor immune microenvironment (TME) of HPD and non-HPD NSCLC patients, aiming to reveal their discrepancies. Methods: Advanced NSCLC patients treated with ICIs in West China Hospital from March 2015 to January 2020 were retrospectively analyzed. HPD was defined as: 1) RECIST progression at first response evaluation, or time-to-treatment failure (TTF) &lt; 2 months; 2) increase in tumor volume &gt; 50%; 3) tumor growth rate (TGR) &gt; 2-fold. Total cellular RNA was extracted from FFPE samples and subjected to gene expression evaluation using NanoString nCounter. A customized code set consisting of a 289-gene panel related to the tumor, immune regulation, and tumor microenvironment was used. Results: A total of 296 patients were screened, including 26 (8.8%) HPD and 272 (91.2%) non-HPD patients. A total of 52 specimens were subjected to TME analysis. At last, data from 27 (8 HPD and 19 non-HPD) samples were suitable for final analysis. We revealed 22 differential expressed genes (DEGs) (fold change &gt; = 2, FDR &lt; 0.05) in the HPD group using DESeq2, including 14 up-regulated genes and 8 down-regulated genes. Gene ontology (GO) enrichment analysis revealed that the DEGs were significantly enriched in leukocyte migration, leukocyte chemotaxis, and neutrophil migration. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results revealed that the DEGs were significantly enriched in IL-17 signaling pathway. Levels and proportions of 16 immune cell types, tumor-infiltrating lymphocytes (TILs) score, cytolytic activity (CYT) score, cytotoxic T lymphocytes (CTL) level, IFN-γ signature, T cell markers, teff score and 18-gene T cell-inflamed GEP score were estimated using characteristic gene expression signatures. We found that immune cells had a lower tendency in the HPD group, and B-cells, CD45, cytotoxic cells, T-cells, and Th1-cells reached significantly lower levels. Further analysis revealed that the HPD group had significantly lower total TILs score, Teff score, and T cell-inflamed GEP score. Conclusions: HPD patients in NSCLC had immune-suppressive TME which were significantly different from non-HPD patients. Patients with low TILs score, Teff score, and T cell-inflamed GEP score may develop HPD and have a poor prognosis after receiving ICIs therapy. The TME signatures in the tissues before ICIs treatment might become a predictive biomarker of HPD risk.
Estimating clear cell renal cell carcinoma transcriptomic signatures using machine learning and histopathology images.
Authors: Saeed Hassanpour, Naofumi Tomita, Ritesh Kotecha, Chung-Han Lee
Journal: Journal of Clinical Oncology (2022)

4533 Background: Gene expression signatures derived from RNA sequencing data have been associated with treatment outcomes for renal cell carcinoma (RCC) patients. Incorporating these RNA biomarkers into clinical practice is promising, yet its real-world applicability is heavily limited as RNA profiling is expensive, time-consuming, and requires specialized expertise for data analysis. In this study, we applied a deep neural network framework to identify the correlation between standard pathology images and underlying RNA signatures using hematoxylin and eosin (H&amp;E) stained formalin-fixed paraffin-embedded (FFPE) whole slides of clear cell kidney tumors from The Cancer Genome Atlas (TCGA). Methods: We collected 496 H&amp;E stained FFPE clear cell RCC whole-slide images and the RNA gene signatures for 496 patients from the TCGA database. We partitioned 496 slides into training (N = 245, 50%), development (N = 49, 10%), and test (N = 202, 40%) sets. We used this dataset to train and evaluate our weakly-supervised deep learning model. The model was iteratively trained using extracted patches from a slide and processed the patches through a convolutional neural network (CNN), pre-trained for the RCC subtypes classification task, to represent features. The features were aggregated and summarized to predict angiogenesis, myeloid infiltration, and adenosine gene signature (AdenoSig) scores. Performance was assessed by computing Pearson’s correlation coefficients. 95% confident intervals (CI) are computed using the Fisher Z transformation. Results: The median angiogenesis score was 6.98 (range: 1.77-8.40), the median myeloid score was 0.54 (range: -4.59-5.96), and the median AdenoSig score was 268.31 (range: -4988.71-7621.57). A total of 202 slides were included in the test set. On this test set, the results of our weakly supervised method achieved a Pearson’s correlation of 0.65 (95% CI: 0.57-0.73), 0.10 (95% CI: -0.04-0.23), and 0.10 (95% CI: -0.04-0.23) with angiogenesis, myeloid, and AdenoSig scores from gold-standard RNA sequencing data, respectively. Conclusions: We proposed using deep learning-based AI techniques to process digitized histopathological images and estimate actionable signatures of angiogenesis, myeloid, and AdenoSig from H&amp;E stained slides. Our model showed promising results for predicting angiogenesis scores compared to myeloid and AdenoSig scores. These results suggest the feasibility of this approach for estimating digital biomarkers from H&amp;E histopathology images and offering a rapid and cost-effective alternative to conventional RNA sequencing.
Robotic-assisted versus manual Uro-Dyna CT-guided puncture in an ex-vivo kidney model
Authors: B. Grüne, R. Burger, D. Bauer, A. Schäfer, A. Rothfuss, J. Stallkamp, M.C. Kriegmair, M-C. Rassweiler-Seyfried
Journal: European Urology (2022)
Characterisation of disease progression in low-risk renal cell carcinoma patients by multiomics data
Authors: P. Strauss, M. Rivedal, A. Scherer, Ø. Eikrem, S. Nakken, C. Beisland, L. Bostad, A. Flatberg, E. Skandalou, V. Beisvag, J. Furriol, H.P. Marti
Journal: European Urology (2022)
Multi-omic and spatial dissection of immunotherapy response groups in non–small cell lung cancer (NSCLC).
Authors: Kenneth John O'Byrne, James Monkman, Honesty Kim, Marie Cumberbatch, Milan Bhagat, Rahul Ladwa, Mark N Adams, Arutha Kulasinghe
Journal: Journal of Clinical Oncology (2022)

8544 Background: Immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The composition of the tumour microenvironment (TME) is becomingly increasingly recognised as an important factor to predict response to therapy. Methods: Here, we applied digital spatial profiling of the tumour and stromal compartments from a 2 nd line NSCLC ICI-treated cohort (n = 41 patient) and standard of care (SOC), platinum treated NSCLC cohort (n = 47), to identify tissue-based signatures of response to therapy. Results: We demonstrate by mIHC that the interaction of CD68 + macrophages with PD1 + , FoxP3 + cells is significantly enriched in ICI refractory tumours (p = 0.012). Patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p = 0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA (p = 0.001) within their stroma. Immuno-inhibitory markers CTLA-4 (p = 0.021) and IDO-1 (p = 0.023) were supressed in ICI-responsive patients. Tumour CD44 (p = 0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of one of its ligands, SPP1 (osteopontin, p = 0.008). Analysis of dysregulated transcripts indicated the potential inhibition of stromal interferon-gamma (IFNγ) activity, estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR = 1.61, p = 0.01), consistent with its depletion in ICI sensitive patients. Similarly, stromal CTLA-4 (HR = 1.78, p = 0.003) and MDSC/M2 macrophage marker ARG1 (HR = 2.37, p = 0.01) were associated with poorer outcome while BAD (HR = 0.5, p = 0.01) appeared protective. The SOC cohort paralleled similar roles for immune checkpoints and pro-apoptotic markers, with LAG3 (HR = 3.81, p = 0.04) indicating poorer outcome, and BIM (HR = 0.16, p = 0.014) with improved outcome. Interestingly, stromal mRNA for E-selectin (HR = 652, p = 0.001), CCL17 (HR = 70, p = 0.006) and MTOR (HR = 1065, p = 0.008) were highly associated with poorer outcome in ICI treated patients, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance. Conclusions: Through multi-modal approaches, we have dissected the characteristics of NSCLC treatment groups and provide evidence for the role of several markers including IL2, CD25, CD44 and SPP1 in the efficacy of current generations of ICI therapy.
RARE-28. The use of subcutaneous interferon in patients with craniopharyngioma: an institutional retrospective review
Authors: Prabhumallikarjun Patil, Rachel Gray, Adam Goldman-Yassen, Dolly Aguilera, Robert Castellino, Anna Janss, Claire Mazewski
Journal: Neuro-Oncology (2022)

Abstract Current strategies for managing craniopharyngioma result in significant morbidity. Successful treatment with interferon alfa(INFα) after progression is reported in the literature. This retrospective review details our institutional experience with INFα in craniopharyngioma patients. Method: Between 2000-2021, we treated 81 craniopharyngioma patients. Twenty-two patients received 26 treatment courses of subcutaneous INFα. Twenty-three courses were evaluable for response. Results: Ten patients received upfront INFα after cyst decompression +/- ommaya placement. Progression free survival(PFS) ranged between 7-38mo. Three patients continue on treatment (10+, 12+, 14+mo); seven progressed (four on treatment (7, 9, 25, 38mo), three after treatment (13, 19, 32mo)). At progression, three underwent surgery alone, three underwent surgery and radiation, one resumed INFα. Thirteen patients received INFα after progression. Prior to INFα, eight patients had had surgery, five surgery and radiation. Two in each group had INFα, previously. PFS ranged between 5-82+mo. One patient remains on treatment (5+mo); four continue in follow-up without progression (23+,40+,64+,82+mo) with two patients avoiding radiation to date; eight progressed (three on treatment (6-8mo), five after treatment (16,24,26,46,71mo)). At progression, two underwent surgery alone, three underwent surgery and radiation, one received re-irradiation, two resumed INFα. While receiving INFα, two patients experienced serious adverse events (one intra-tumoral hemorrhage (not attributed to INFα), one suicidal ideation). Both recovered. One tolerated retreatment with INFα. Three additional patients stopped INFα for intolerance, but two received INFα at subsequent progression. No other unanticipated side effects were reported. Conclusion: INFα therapy in patients with both newly diagnosed and progressive craniopharyngioma delayed the need for aggressive surgical resection and/or radiotherapy in some cases. In some patients, INFα resulted in prolonged stabilization of disease delaying or avoiding radiation. Overall, INFα side effects were manageable. These results are encouraging regarding INFα therapy for patients with craniopharyngioma and warrant further evaluation with a clinical trial.
Exploring the diversity and predictors of histopathological findings across the European Association of Urology Guidelines Office rapid reaction group priority groups for patients with renal tumours: Implications for prioritization of renal cancer care
Authors: R. Campi, A. Pecoraro, R. Tellini, A.A. Grosso, M. Andrea, M.R. Raspollini, M. Gacci, M. Carini, A. Minervini
Journal: European Urology (2022)
Correction to “Spatiotemporally dynamic therapy with shape-adaptive drug-gel for the improvement of tissue regeneration with ordered structure” [Bioact. Mater. 8 (2022) 165–176]
Authors: Ya-nan Fu, Yongsan Li, Bo Deng, Yingjie Yu, Fang Liu, Lei Wang, Guang Chen, Lei Tao, Yen Wei, Xing Wang
Journal: Bioactive Materials (2022)

[This corrects the article DOI: 10.1016/j.bioactmat.2021.06.015.].
Lipidomic analysis of seminal plasma in patients with non-obstructive azoospermia
Authors: A.K. Tambiev, V.V. Chagovets, T. Shatylko, A.O. Tokareva, S.I. Gamidov, N.L. Starodubtseva, A.Y. Popova, V.E. Frankevich
Journal: European Urology (2022)
First-line lenvatinib plus pembrolizumab plus chemotherapy in esophageal squamous cell carcinoma: LEAP-014 trial in progress.
Authors: Jong-Mu Sun, Peter C. Enzinger, Antoine Adenis, Manish A. Shah, Ken Kato, Jaafar Bennouna, Toshihiko Doi, Natalyn Nicole Hawk, Li Yu, Sukrut Shah, Pooja Bhagia, Lin Shen
Journal: Journal of Clinical Oncology (2022)

TPS4167 Background: Recent data from the KEYNOTE-590 study demonstrated the superiority of pembrolizumab plus chemotherapy compared with chemotherapy as first-line treatment for unresectable locally advanced recurrent or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction. Prior data also suggest promising antitumor activity of lenvatinib plus pembrolizumab in advanced solid tumors. LEAP-014 (NCT04949256) is a randomized, 2-part, open-label, phase 3 study that will evaluate the efficacy and safety of first-line lenvatinib plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with metastatic esophageal squamous cell carcinoma (ESCC). Methods: Key eligibility criteria include histologically or cytologically confirmed metastatic ESCC, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and Eastern Cooperative Oncology Group performance status 0 to 1. In part 1 (safety run-in), ̃6 patients will be treated for induction with intravenous (IV) pembrolizumab 400 mg every 6 weeks (Q6W) for 2 cycles plus oral lenvatinib 8 mg daily (QD) plus IV 5-fluorouracil (FU; 4000 mg/m 2 on days 1-5) plus IV cisplatin (80 mg/m 2 ) (FP) for 4 cycles and treated for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD; patients will be closely monitored for 21 days after the first dose of study intervention for dose-limiting toxicities. In part 2 (main study), approximately 850 patients will be randomly assigned 1:1 to induction with pembrolizumab plus lenvatinib plus chemotherapy (FP or mFOLFOX6 [Q2W for 6 cycles {IV oxaliplatin 85 mg/m 2 plus bolus IV 5-FU 400 mg/m 2 plus continuous IV 5-FU 2400 mg/m 2 plus IV leucovorin 400 mg/m 2 or IV levoleucovorin 200 mg/m 2 }]) followed by consolidation with pembrolizumab plus lenvatinib (arm 1) or pembrolizumab plus chemotherapy (FP or mFOLFOX6; arm 2). Randomization will be stratified by PD-L1 combined positive score (CPS; ≥10 vs &lt; 10), region (East Asia vs North America and Western Europe vs rest of world), and chemotherapy backbone (FP vs mFOLFOX6). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor imaging assessment will be performed Q6W for ≤1 year and Q9W thereafter. In part 1, the primary end point is safety and tolerability. In part 2, the dual primary end points are overall survival and progression-free survival (per RECIST v1.1 assessed by blinded independent central review [BICR]); secondary end points include objective response rate and duration of response (per RECIST v1.1 assessed by BICR) and safety and tolerability. Enrollment in this trial is ongoing. Clinical trial information: NCT04949256.